Use of certain drugs for treating nerve root injury

ABSTRACT

The present invention relates to pharmaceutical compositions for the treatment of spinal disorders caused by the liberation of TNF-alpha comprising an effective amount of a TNF-alpha inhibitor, as well as a method for treatment of such disorders, and the use of TNF-alpha inhibitors in the preparation of pharmaceutical compositions for such treatment.

This application is a National Stage of International Application No.PCT/SE99/01671, filed Sep. 23, 1999 in English, which claims benefit ofSwedish applications 9803276-6 and 9803710-04 filed respectively on Sep.25, 1998 and Oct. 29, 1998 in English.

TECHNICAL FIELD

The present invention relates to the use of a TNF-α inhibitor in thepreparation of pharmaceutical compositions for the treatment of nerveroot injury, as well as a method for treating nerve root injury.

The object of the present invention is to obtain a possibility to treatnerve root injury induced by disk herniation, which may turn up asradiating pain into the arm or leg (sciatica), by blocking disk relatedcytokines.

BACKGROUND OF THE INVENTION

Disk herniation is a troublesome disorder, which can cause pronouncedpain and muscle dysfuntion, and thereby loss of ability to work. Aherniation may occur in any disk in the spine but herniations in thelumbar and the cervical spine are most common. A disk herniation in thecervical spine may induce radiating pain and muscle dysfunction in thearm and herniation in the lumbar spine may induce radiating pain andmuscle dysfunction in the leg. The radiating pain in the leg isgenerally referred to as “sciatica”. Disk herniation will cause troubleto a varying degree, and the pain may last for one or two months or insevere cases up to 6 months. The arm or leg pain that can occur as aresult of disk herniation can be very intense and may thus affect theindividual patient's whole life situation during the sickness period.

U.S. Pat. No. 5,703,092 discloses the use of hydroxamic acid compoundsand carbocyclic acids as metalloproteinase and TNF inhibitors, and inparticular in treatment of arthritis and other related inflammatorydiseases. No use of these compounds for the treatment of nerve rootinjuries is disclosed or hinted at.

U.S. Pat. No. 4,925,833 discloses the use of tetracyclines to enhancebone protein synthesis, and treatment of osteoporosis.

U.S. Pat. No. 4,666,897 discloses inhibition of mammalian collagenolyticenzymes by tetracyclines. The collagenolytic activity is manifested byexcessive bone resorption, periodontal disease, rheumatoid arthritis,ulceration of cornea, or resorption of skin or other connective tissuecollagen.

Neither of these latter two documents mentions nerve root injury or thetreatment thereof.

DESCRIPTION OF THE PRESENT INVENTION

It has now surprisingly been shown possible to be able to treat nerveroot injuries, or at least alleviate the symptoms of nerve root injuriesby using a pharmaceutical composition comprising an therapeuticallyactive amount of a TNF-α inhibitor selected from the group consisting ofmetalloproteinase inhibitors excluding methylprenisolone, tetracyclinesincluding chemically modified tetracyclines, quinolones,corticosteroids, thalidomide, lazaroides, pentoxyphylline, hydroxamicacid derivatives, napthopyrans, soluble cytokine receptors, monoclonalantibodies towards TNF-α, amrinone, pimobendan, vesnarinone,phosphodiesterase III inhibitors, lactoferrin and lactoferrin derivedanalogous, and melatonin in the form of bases or addition salts togetherwith a pharmaceutically acceptable carrier.

The therapeutically effective amount is a dosage normally used whenusing such compounds for other therapeutic uses. Many of these drugs arecommercially known registered drugs.

Compounds that possess this activity are tetracyclines, such astetracycline, doxycycline, lymecycline, oxytetracycline, minocycline,and chemically modified tetracyclines dedimethylaminotetracycline,hydroxamnic acid compounds, carbocyclic acids and derivatives,thalidomide, lazaroides, pentoxyphylline, napthopyrans, soluble cytokinereceptors, monoclonal antibodies towards TNF-α, amrinone, pimobendan,vesnarinone, phosphodiesterase III inhibitors, lactoferrin andlactoferrin derived analogous, melatonin, norfloxacine, ofloxacine,ciprofloxacine, gatifloxacine, pefloxacine, lomefloxacine, andtemafloxacine. These can be present as bases or in the form of additionsalts, whichever possesses the best pharmaceutical effect, and bestproperty to be brought into a pharmaceutical suitable composition.

After previously being considered as just a biologically inactive tissuecomponent compressing the spinal nerve root at disc herniation, thenucleus pulposus has recently been found to be highly active, inducingboth structural and functional changes in adjacent nerve roots whenapplied epidurally (24, 37, 38, 41, 42). It has thereby been establishedthat autologous nucleus pulposus may induce axonal changes and acharacteristic myelin injury (24, 38, 41, 42), increased vascularpermeability (9, 44), intra vascular coagulation (24, 36), and thatmembrane-bound structure or substances of the nucleus pulposus-cells areresponsible for these effects (24, 37). The effects have also been foundto be efficiently blocked by methyl-prednisolone and cyclosporin A (2,38). When critically looking at these data, one realizes that there isat least one cytokine that relates to all of these effects, TumorNecrosis Factor alpha (TNF-α). Further, the active component comprises asubstance inhibiting a compound triggered by the release of TNF-α, suchas interferon-gamma, interleukin-1, and nitrogen oxide (NO) in the formof base or addition salts.

The invention further relates to a method for inhibiting the symptoms ofnerve root injury.

The effects of doxycycline, soluble cytokine-receptors, and monoclonalcytokine-antibodies have been studied and the methods used and resultsobtained are disclosed below.

EXAMPLE Study Design

The effects of nucleus pulposus and various treatments to block TNF-αactivity were evaluated in an experimental set-up usingimmunohistochemistry and nerve conduction velocity recordings.

SUMMARY OF BACKGROUND DATA

A meta-analysis of observed effects induced by nucleus pulposus revealsthat these effects might relate to one specific cytokine, Tumor NecrosisFactor alpha (TNF(α).

Objectives

To assess the presence of TNF(α) in pig nucleus pulposus cells and tosee if blockage of TNF(α) also blocks the nucleus pulposus-inducedreduction of nerve root conduction velocity.

Methods

Series-1

Cultured nucleus pulposus-cells were immunohistologically stained with amonoclonal antibody for TNF(α).

Series-2

Nucleus pulposus was harvested from lumbar discs and applied to thesacrococcygeal cauda equina in 13 pigs autologously. Four pigs received100 mg of doxycycline intravenously, 5 pigs had a blocking monoclonalantibody to TNF-α applied locally in the nucleus pulposus, and 4 pigsremained non-treated and formed control. Three days after theapplication the nerve root conduction velocity was determined over theapplication zone by local electrical stimulation.

Series-3

Thirteen pigs had autologous nucleus pulposus placed onto theirsacrococcygeal cauda equina similar to series-2. Five pigs (bodyweight25 kg) received REMICADE (infliximab) 100 mg i.v. preoperatively, and 8pigs received ENBREL (etanercept) 12.5 mg s.c. preoperatively andadditionally 12.5 mg s.c. three days after the operation. Seven daysafter the nucleus pulposus-application the nerve root conductionvelocity was determined over the application zone by local electricalstimulation according to series-2.

Results

Series-1

TNF-α was found to be present in the nucleus pulposus-cells.

Series-2

The selective antibody to TNF-α limited the reduction of nerveconduction velocity, although not statistically significantly to thecontrol series. However, treatment with doxycycline significantlyblocked the nucleus pulposus-induced reduction of conduction velocity.

Series-3

Both drugs (infliximab, and etanercept) blocked the nucleus pulposusinduced nerve injury efficiently and normal average nerve conductionvelocities were found after treatment with both of these two drugs.

Conclusion

For the first time a specific substance, Tumor Necrosis Factor-alpha,has been linked to the nucleus pulposus-induced effects of nerve rootsafter local application. Although the effects of this substance may besynergistic with other similar substances, the data of the present studymay be of significant importance for the continued understanding ofnucleus pulposus' biologic activity, and might also be of potential usefor future treatment strategies of sciatica.

After previously being considered as just a biologically inactive tissuecomponent compressing the spinal nerve root at disc herniation, thenucleus pulposus has recently been found to be highly active, inducingboth structural and functional changes in adjacent nerve roots whenapplied epidurally (24, 37, 38, 41, 42). It has thereby been establishedthat autologous nucleus pulposus may induce axonal changes and acharacteristic myelin injury (24, 38, 41, 42), increased vascularpermeability (9, 44), intra vascular coagulation (24, 36), and thatmembrane-bound structure or substances of the nucleus pulposus-cells areresponsible for these effects (24, 37). The effects have also been foundto be efficiently blocked by methyl-prednisolone and cyclosporin A (2,38). When critically looking at these data, one realizes that there isat least one cytokine that relates to all of these effects. TumorNecrosis Factor alpha (TNF-α). To assess if TNF-α may be involved in thenucleus pulposus induced nerve root injury, the presence of TNF-α innucleus pulposus-cells was assessed by studying if the nucleuspulposus-induced effects could be blocked by doxycycline, a solubleTNF-receptor, and a selective monoclonal TNF-antibody, The latter wasadministered both locally in the nucleus pulposus and systemically.

MATERIAL AND METHODS

Series-1, Presence of TNF-α in Pig Nucleus Pulposus-cells

Nucleus pulposus (NP) from a total of 13 lumbar and thoracic discs wereobtained from a pig used for other purposes. NP was washed once in Ham'sF12 medium (Gibco BRL, Paisley, Scotland) and then centrifuged andsuspended in 5 ml of collagenase solution in Ham's F12 medium (0.8mg/ml, Sigma Chemical Co., St Louis, Mo., USA) for 40 minutes, at 37° C.in 25 cm² tissue culture flasks. The separated NP-cell pellets weresuspended in DMEM/F12 1:1 medium (Gibco BRL, Paisley, Scotland)supplemented with 1% L-glutamine 200 mM (Gibco BRL, Paisley, Scotland),50 Mg/ml gentamycine sulphate (Gibco BRL, Paisley, Scotland) and 10%foetal calf serum (FCS), (Gibco BRL, Paisley, Scotland). The cells werecultured at 37° C. and 5% CO₂ in air for 3-4 weeks and then cultureddirectly on tissue culture treated glass slides (Becton Dickinson & CoLabware, Franklin Lakes, N.J., USA). After 5 days on the glass slides,the cells were fixed in situ by acetone for 10 minutes. After blockingirrelevant antigens by application of 3% H₂O₂ (Sigma Chemical Co., StLouis, Mo., USA) for 30 minutes and Horse Serum (ImmunoPure ABC,peroxidase mouse IgG staining kit nr.32028, Pierce, Rockford, Ill.) for20 minutes, the primary antibody (Anti-pig TNF-α monoclonal purifiedantibody, Endogen, Cambridge, Mass., USA) was applied over night at +40°C., diluted at 1:10, 1:20 and 1:40. For control, BSA (bovine serumalbumin, Intergen Co, New York, USA) suspended in PBS (phosphatebuffered saline, Merck, Darmstadt, Germany) was applied in the samefashion. The next day the cells were washed with 1% BSA in PBS and thesecondary antibody (Immunopure ABC, peroxidase mouse IgG staining kitnr.32028, Pierce, Rockford, Ill.) was applied for 30 minutes. To enhancethis reaction, the cells were exposed to Avidin-Biotin complex foradditionally 30 minutes (ImmunoPure ABC, peroxidase mouse IgG stainingkit nr.32028, Pierce, Rockford, Ill.). The cells were then exposed to 20mg of DAB (3,3-diaminobenzidine tetrahydrochloride nr. D-5905, SigmaChemical Co., St Louis, Mo., USA) and 0.033 ml of 3% H₂O₂ in 10 ml ofsaline for 10 minutes. The cells were washed in PBS, dehydrated in aseries of ethanol, mounted and examined by light microscopy by anunbiased observer regarding the presence of a brown colourationindicating presence of TNF-α.

Series-2, Neurophysiologic Evaluation

Thirteen pigs, (body weight 25-30 kg) received an intramuscularinjection of 20 mg/kg body weight of KETALAR® (ketamine 50 mg/ml,Parke-Davis, Morris Plains, N.J.) and an intravenous injection of 4mg/kg body weight of Hypnodil^(R) (methomidate chloride 50 mg/ml, A BLeo, Helsingborg, Sweden) and 0.1 mg/kg body weight of STRESNIL®(azaperon 2 mg/ml, Janssen Pharmaceutica, Beerse, Belgium). Anaesthesiawas maintained by additional intravenous injections of 2 mg/kg bodyweight of HYPNODIL® and 0.05 mg/kg body weight of STRESNIL®. The pigsalso received an intravenous injection of 0.1 mg/kg of STESOLID® NOVUM®(Diazepam, Dumex, Helsingborg, Sweden) after surgery.

Nucleus pulposus was harvested from the 5th lumbar disc through a retroperitoneal approach (42). Approximately 40 mg of the nucleus pulposuswas applied to the sacrococcygeal cauda equina through a midlineincision and laminectomy of the first coccygeal vertebra. Four pigs didnot receive any treatment (no treatment). Four other pigs received anintravenous infusion of 100 mg of doxycycline (Vibramycino, Pfizer Inc.,New York, USA) in 100 ml of saline over 1 hour. In 5 pigs, the nucleuspulposus was mixed with 100 μl of a 1.11 mg/ml suspension of theanti-TNF-α antibody used in Series 1, before application.

Three days after the application, the pigs were reanaesthetized by anintramuscular injection of 20 mg/kg body weight of KETALAR® and anintravenous injection of 35 mg/kg body weight of PENTOTHAL® (Thiopentalsodium, Abbott lab, Chicago, Ill.). The pigs were ventilated on arespirator. Anaesthesia was maintained by an intravenous bolus injectionof 100 mg/kg body weight of Chloralose (α)-D(+)-gluco-chloralose, Merck,Darmstadt, Germany) and by a continuous supply of 30 mg/kg/hour ofChloralose. A laminectomy from the 4th sacral to the 3rd coccygealvertebra was performed. The nerve roots were covered with SPONGOSTANE®(Ferrosan, Demnark). Local tissue temperature was continuously monitoredand maintained at 37.5-38.0° C. by means of a heating lamp.

The cauda equina was stimulated by two E2 subdermal platinum needleelectrodes (Grass Instrument Co., Quincy, Mass.) which were connected toa Grass SD9 stimulator (Grass Instrument Co., Quincy, Mass.) and gentlyplaced intermittently on the cauda equina first 10 mm cranial and then10 mm caudal to the exposed area. To ensure that only impulses fromexposed nerve fibres were registered, the nerve root that exited fromthe spinal canal between the two stimulation sites were cut. An EMG wasregistered by two subdermal platinum needle electrodes which were placedinto the paraspinal muscles in the tail approximately 10 mm apart. Thisprocedure is reproducible and represents a functional measurement of themotor nerve fibres of the cauda equina nerve roots. The EMG wasvisualized using a Macintosh IIci computer provided with Superscopesoftware and MacAdios II AID converter (GW Instruments, Sommerville,Mass.) together with a Grass P18 preamplifier (Grass Instrument Co.,Quincy, Mass.). The separation distance between the first peaks of theEMG from the two recordings was determined and the separation distancebetween the two stimulation sites on the cauda equina was measured withcalipers. The nerve conduction velocity between the two stimulationsites could thus be calculated from these two measurements.

The person performing the neurophysiologic analyses was unaware of theexperimental protocol for the individual animal, and after finishing thecomplete study the data were arranged in the three experimental groupsand statistical differences between the groups were assessed byStudent's t-test. The experimental protocol for this experiment wasapproved by the local animal research ethics committee.

Series-3

Thirteen pigs had autologous nucleus pulposus placed onto theirsacrococcygeal cauda equina similar, to series-2. Five pigs (bodyweight25 kg) received the human/murine monoclonal antibody REMICADE®(infliximab, Immunex Corporation, Seattle, Wash. 98101, USA) 100 mg i.v.preoperatively, and 8 pigs received ENBREL® (etanercept, Centocor B.V.,Leiden, the Netherlands) 12.5 mg s.c. preoperatively and additionally12.5 mg s.c. three days after the operation. Seven days after thenucleus pulposus-application the nerve root conduction velocity wasdetermined over the application zone by local electrical stimulationaccording to series-2. To blind the study the neurophysiologicalevaluation was conducted in parallel to another study and the personperforming the analyses did not know from which study and what treatmenteach specific animal was subjected to. No non-treated animals wereincluded in the series-3 due to the pre-existing knowledge of nerveconduction velocity after seven days of either nucleus pulposus or fat(control) application. The statistical difference between the groups,infliximab, and etanercept, nucleus pulposus without treatment (positivecontrol from previous data) and application of retroperitoneal fat(negative control from previous data) was assessed by using ANOVA andFisher's PLSD at 5%.

RESULTS

Series-1, Presence of TNF-α in Pig Nucleus Pulposus-cells

Examples of the light microscopic appearance of the stained glassslides. In the sections using BSA in PBS as “primary antibody” (control)no staining was observed, ensuring that there was no labelling andvisualization of irrelevant antigens. When the anti-TNF-α antibody wasapplied at 1:40 dilution there was only a weak staining. However, thestaining increased with diminishing dilutions of the antibody. Thestaining was seen in the soma of the cells and it was not possible todifferentiate whether TNF-α was located in the cytoplasm, on the cellsurface bound to the cell-membrane, or both.

Series-2, Neurophysiologic Evaluation

Application of non-modified nucleus pulposus and without any treatmentinduced a reduction in nerve conduction velocity similar to previousstudies (Table 1), whereas treatment with doxycycline completely blockedthis reduction (p<0.0l Student's t-test). Local application ofanti-TNF-α-antibody also induced a partial block of this reduction,although not as complete as doxycycline and not statisticallysignificant to the no treatment-series.

Series-3

Treatment with both drugs seemed to prevent the nucleus pulposus-inducedreduction of nerve root conduction velocities since the average nerveconduction velocity for both these treatment groups were close to theaverage conduction of fat-application series as seen in a previous study(Table 2). There was a statistically significant difference toapplication of nucleus pulposus, but without any treatment, seen forboth drugs.

TABLE 1 Series-2 Treatment n NCV (m/s + SD) Local anti-TN-α 5 64 ± 28Doxycycline 4 76 ± 9  No treatment 4 46 ± 12

TABLE 2 Series-3 Treatment n NCV (m/s + SD) Fat* 5 76 ± 11 EMBREL ® 8 78± 14 REMICADE ® 5 79 ± 15 No treatment* 5 45 ± 19 *Data included fromref. no. 42, Olmarker et al, 1993

DISCUSSION

The data of the present study demonstrated that TNF-α may be found innucleus pulposus-cells of the pig. If TNF-α was blocked by a locallyapplied selective monoclonal antibody, the nucleus pulposus-inducedreduction of nerve root conduction velocity was partially blocked,although not statistically significant compared to the series withnon-treated animals. However, if systemic treatments with doxycycline,infliximab, and etanercept were used to inhibit TNF-α, the reduction ofnerve conduction velocity was significantly prevented.

In recent years, it has been verified that local application ofautologous nucleus pulposus may injure the adjacent nerve roots. Thus,it has become evident that the nerve root injury seen as disc herniationmay not be solely based on mechanical deformation of the nerve root, butmay also be induced by unknown “biochemical effects” related to theepidural presence of herniated nucleus pulposus. Although this newresearch field has generated many experimental studies, the mechanismsand substances involved are not fully known. It has been seen that localapplication of autologous nucleus pulposus may induce axonal injury(24,37,38,40-42), a characteristic injury of the myelin sheath(24,38,40-42), a local increase of vascular permeability (9,36,44),intra vascular coagulations, reduction of intra neural blood flow (43),and leukotaxis (36). It has been seen that the nucleus pulposus-relatedeffects may be blocked efficiently by methylprednisolone (38) andcyclosporin A (2), and slightly less efficiently by indomethacin (3),and lidocaine (69). Further, it has been understood that the effects aremediated by the nucleus pulposus-cells (37), particularly by substancesor structures bound to the cell-membranes (25). When criticallyconsidering these data, it becomes evident that at least one specificcytokine could be related to these observed effects, Tumor NecrosisFactor-alpha (TNF-α). TNF-α may induce nerve injury (29,31,45,50,66)mainly seen as a characteristic myelin injury that closely resembles thenucleus pulposus-induced myelin-injury (29,47,51,54,62,64,66,70).TNF-αmay also induce an increase in vascular permeability (47,66) andinitiate coagulation (22,34,63). Further, TNF-α may be blocked bysteroids (4,8,21,61,68), and cyclosporin A (11,55,67,68). However, theblocking effect on TNF-α is not so pronounced by NSAID (14,17,20) andvery low or the opposite by lidocaine (5,32,46,60). It was recentlyobserved that local application of nucleus pulposus may inducepain-related behaviour in rats, particularly thermal hyperalgesia(23,40). TNF-α has also been found to be related to suchpain-behaviouristic changes (12,35,56,66), and also to neuropathies ingeneral (30,54,56,57). However there are no studies that have assessedthe possible presence of TNF-α in the cells of the nucleus pulposus.

To assess if TNF-α could be related to the observed nucleus pulposusinduced reduction in nerve root conduction velocity it was necessaryfirst to analyse if there was TNF-α in the nucleus pulposus-cells. Thedata clearly demonstrated that TNF-α was present in these cells. TNF-αis produced as precursor (pro-TNF) that is bound to the membrane and itis activated by cleavage from the cell-membrane by a zinc-dependentmetallo-endopeptidase (TNF-α converting enzyme, TACE) (6,15,16,48,49).This may thus relate well to experimental findings where application ofthe mere cell-membranes of autologous nucleus pulposus-cells inducednerve conduction velocity reduction, which indicated that the effectswere mediated by a membrane-bound substances. Second, the effects of theTNF-α had to be blocked in a controlled manner. We then first chose toadd the same selective antibody that was used for immunohistochemistryin series 1, which is known to also block the effects of TNF-α, to thenucleus pulposus before application. Also, we chose to treat the pigswith doxycycline, which is known to block TNF-α (26,27,33,52,53).However, due to the low pH of the doxycycline preparation it was chosento treat the pigs by intravenous injection instead of local addition tothe nucleus pulposus since nucleus pulposus at a low pH has been foundto potentiate the effects of the nucleus pulposus (38,39).

Two recently developed drugs for specific TNF-α inhibition were alsoincluded in the study.

Infliximab is a chimeric monoclonal antibody composed of human constantand murine variable regions, and binds specifically to human TNF-α. Asopposed to the monoclonal antibody used in series-2 for the 3 daysobservation period, infliximab was not administered locally in theautotransplanted nucleus pulposus but instead systemically in aclinically recommended dose (4 mg/kg). Etanercept is a dimeric fusionprotein consisting of the Fc portion of human IgG. The drug wasadministered in a dosage comparable to the recommended dose forpediatric use (0.5 mg/kg, twice a week).

The data regarding nerve conduction velocity showed that the reductionwas completely blocked by the systemic-treatment and that the nerveconduction velocities in these series were close to the conductionvelocity after application of a control substance (retro peritoneal fat)from a previous study (42). Application of the anti-TNF-α-antibody tothe nucleus pulposus also partially prevented the reduction in nerveconduction velocity, however, not as pronounced as doxycycline, and thevelocity in this series was not statistically different to the velocityin the series with not treated animals, due to the wide deviation of thedata.

The fact that the local anti-TNF-α antibody treatment only partiallyblocked the nucleus pulposus-induced reduction of nerve conductionvelocity and the high standard deviation of the data could probably haveat least three different explanations. First, if looking at the specificdata within this group it was found that the nerve conduction velocitywas low in 2 animals (mean 37.5 m/s) and high in 3 animals (mean 81.3m/s). There are thus 2 groups of distinctly different data within theanti-TNF-α treatment series. This will account for the high standarddeviation and might imply that the blocking effect was sufficient in 3animals and non-sufficient in 2 animals. The lack of effects in theseanimals could be based simply on the amount of antibodies in relation toTNF-α molecules not being sufficient, and if a higher dose of theantibody had been used, the TNF-α effects would thus have been blockedeven in these animals. Such a scenario could then theoretically implythat TNF-α alone is responsible for the observed nucleuspulposus-induced effects, and that this could not be verifiedexperimentally due to the amount of antibody being too low.

Second, it is also known that tetracyclines such as doxycycline andminocycline may block a number of cytokines and other substances. Forinstance they may block IL-1 (1,28,58), IFNγ (27), NO-synthetasel, andmetalloproteinases (1,53,58). Particularly IL-1 and IFNγ are known toact synergistically with TNF-α and are known to be more or lessneurotoxic (7,10,13,18,19,56,59). These substances, are also blocked bysteroids and cyclosporin A which corresponds well with the previousobservations on nucleus pulposus-induced nerve root injury which haveshown that the nucleus pulposus-induced effects may be blocked by thesesubstances (8,67). One may therefore also consider the possibility thata selective block of TNF-α may not be sufficient to completely block thenucleus pulposus-induced effects on nerve function, and thatsimultaneous block of other synergistic substances is necessary as well.Thus, this scenario, on the other hand, implies that TNF-α is not solelyresponsible for the nucleus pulposus-induced effects, and that othersynergistic substances, which are also blocked by doxycycline, may benecessary.

The third explanation could be that the amount of TNF in the nucleuspulposus may well be enough to start the pathophysiologic cascadelocally in the nerve root, comprising increased vascular permeabilityand aggregation and recruitment of systemic leukocytes. However, it isthese leukocytes that have the major content of TNF-α and that systemictreatment in a sufficient dose is necessary to block the contributionfrom these leukocytes, and thereby also blocking the events leading tonerve injury.

TNF-α may have various pathophysiologic effects. It may have directeffects on tissues such as nerve tissue and blood vessels, it maytrigger other cells to produce other pathogenic substances and it maytrigger release of more TNF-α both by inflammatory cells and also bySchwann-cells locally in the nerve tissue (65). There is thus reason tobelieve that even low amounts of TNF-α may be sufficient to initiatethese processes and that there is a local recruitment of cytokineproducing cells and a subsequent increase in production and release ofother cytokines as well as TNF-α. TNF-α may therefore act as the“ignition key” of the pathophysiologic processes and play an importantrole for the initiation of the pathophysiologic cascade behind thenucleus pulposus-induced nerve injury. However, the major contributionof TNF-α may be derived from recruited, aggregated and maybe evenextravasated leukocytes, and that successful pharmacologic block may beachieved only by systemic treatment.

In conclusion, although the exact role of TNF-α can not be fullyunderstood from the experimental set-up, we may conclude that for thefirst time a specific substance (TNF-α) has been linked to the nucleuspulposus-induced nerve root injury. This new information may be ofsignificant importance for the continued understanding of nucleuspulposus-induced nerve injury as well as raising the question of thepotential future clinical use of pharmacological interference with TNF-αand related substances, for treatment of sciatica.

The presence of TNF-α in pig nucleus pulposus-cells was thusimmunohistochemically verified. Block of TNF-α by a locally appliedmonoclonal antibody partially limited the nucleus pulposus-inducedreduction of nerve root conduction velocity, whereas intravenoustreatment with doxycycline, infliximab, and etanercept significantlyblocked this reduction. These data for the first time links one specificsubstance, TNF-α, to the nucleus pulposus-induced nerve injury.

Aminoguanidine has showed to inhibit the release of nitrogen oxide (NO)at nerve root injuries by inhibiting inducible nitrogen oxidesynthetase, and aminoguanidine is thus one compound that inhibits acompound trigged by the release of TNF-α.

The compounds of the invention can be administered in a variety ofdosage forms, e.g, orally, in the form of tablets, capsules, sugar orfilm coated tablets, liquid solutions; rectally, in the form ofsuppositories; parenterally, e.g., intramuscularly or by intravenousinjection or infusion. The therapeutic regimen for the differentclinical syndromes must be adapted to the type of pathology taken in toaccount, as usual, also the route of administration, the form in whichthe compound is administered and age, weight, and condition of thesubject involved.

The oral route is employed, in general, for all conditions, requiringsuch compounds. In emergency cases preference is given to intravenousinjection. For these purposes the compounds of the invention can beadministered orally at doses ranging from about 20 to about 1500 mg/day.Of course, these dosage regimens may be adjusted to provide the optimaltherapeutic response.

The nature of the pharmaceutical composition containing the compounds ofthe invention in association with pharmaceutically acceptable carriersor diluents will, of course, depend upon the desired route ofadministration. The composition may be formulated in the conventionalmanner with the usual ingredients. For example, the compounds of theinvention may be administered in the form of aqueous or oily solutionsor suspensions, tablets, pills, gelatine capsules (hard or softones)syrups, drops or suppositories.

Thus for oral administration, the pharmaceutical compositions containingthe compounds of the invention are preferably tablets, pills or gelatinecapsules, which contain the active substance together with diluents,such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose;lubricants, e.g., silica, talc, stearic acid, magnesium or calciumstearate, and/or polyethylene glycols; or they may also contain binders,such as starches, gelatine, methyl cellulose, carboxymethylcellulose,gum arabic, tragacanth, polyvinylpyrrolidone; disaggregating agents suchas starches, alginic acid, alginates, sodium starch glycolate,microcrystalline cellulose; effervescing agents such a carbonates andacids; dyestoffs; sweeteners; wetting agents, such as lecithin,polysorbates, laurylsulphates; and in general non-toxic andpharmaceutically inert substances used in the formulation ofpharmaceutical compositions. Said pharmaceutical compositions may bemanufactured in known manners, e.g., by means of mixing, granulating,tableting, sugar-coating or film-coating processes. In the case filmproviding compounds can be selected to provide release in the rightplace in the intestinal tract with regard to absorption and maximumeffect. Thus pH-dependent film formers can be used to allow absorptionin the intestines as such, whereby different phthalate are normally usedor acrylic acid/methacrylic acid derivatives and polymers.

The liquid dispersions for oral administration may be e.g., syrups,emulsion, and suspensions.

The syrups may contain as carrier, e.g., saccharose, or saccharose withglycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as carrier, e.g., a natural gum,such as gum arabic, xanthan gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, polyvinyl alcohol.

The suspension or solutions for intramuscular injections may containtogether with the active compound, a pharmaceutically acceptablecarrier, such as e.g., sterile water, olive oil, ethyl oleate, glycols,e.g., propylene glycol, and if so desired, a suitable amount oflidocaine hydrochloride. Adjuvants for trigging the injection effect canbe added as well.

The solutions for intravenous injection or infusion may contain ascarrier, e.g., sterile water, or preferably, a sterile isotonic salinesolution, as well as adjuvants used in the field of injection of activecompounds.

The suppositories may contain together with the active compound, apharmaceutically acceptable carrier, e.g., cocoa-butter polyethyleneglycol, a polyethylene sorbitan fatty acid ester surfactant or lecithin.

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What is claimed is:
 1. A method of treating a nerve disorder mediated bynucleus pulposus in a mammal in need of such treatment, wherein saidnerve disorder mediated by nucleus pulposus is caused by the liberationof TNF-α and compounds triggerd by the liberation of or presence ofTNF-α, comprising the step of: (A) administering a TNF-α inhibitor,wherein said TNF-α inhibitor is (i) a soluble cytokine receptor thatblocks TNF-α activity, (ii) a monoclonal antibody that blocks TNF-αactivity, or (iii) a tetracycline or a chemically modified tetracyclinethat blocks TNF-α activity, to said mammal in need of such treatmentthereby inhibiting TNF-α and treating said disorder.
 2. The method ofclaim 1, wherein the mammal is human.
 3. The method of claim 1, whereinthe tetracycline or chemically modified tetracycline is selected fromthe group consisting of: tetracycline, doxycycline, lymecycline,oxytetracycline, minocycline, dedimethylaminotetracycline and bases andsalts thereof.
 4. The method of claim 1, wherein said nerve disorder isnerve root injury.
 5. The method of claim 4, wherein said nerve disorderinvolves pain.
 6. The method of claim 4, wherein the mammal is human. 7.The method of claim 4, wherein the tetracycline or chemically modifiedtetracycline is selected from the group consisting of: tetracycline,doxycycline, lymecycline, oxytetracycline, minocycline,dedimethylaminotetracycline and bases and salts thereof.
 8. The methodof claim 4, wherein said TNF-alpha inhibitor is administeredsystemically or locally.
 9. The method of claim 4, wherein saidTNF-alpha inhibitor is administered parenterally.
 10. The method ofclaim 4, wherein said TNF-alpha inhibitor is administeredintramuscularly (i.m.), intravenously (i.v.), subcutaneously (s.c.)orally or rectally.
 11. The method of claim 10, wherein said TNF-alphainhibitor is administered i.v. by injection or infusion.
 12. The methodof claim 10, wherein said TNF-alpha inhibitor is administered orally ata dosage of about 20 mg to about 1,500 mg.
 13. The method of claim 4,wherein said TNF-alpha inhibitor is tetracycline and is administered ata dosage of about 100 mg.
 14. The method of claim 1, wherein said nervedisorder is caused by a herniated disc.
 15. The method of claim 14,wherein said nerve disorder involves pain.
 16. The method of claim 14,wherein the mammal is human.
 17. The method of claim 14, wherein thetetracycline or chemically modified tetracycline is selected from thegroup consisting of: tetracycline, doxycycline, lymecycline,oxytetracycline, minocycline, dedimethylaminotetracycline and bases andsalts thereof.
 18. The method of claim 14, wherein said TNF-alphainhibitor is administered systemically or locally.
 19. The method ofclaim 14, wherein said TNF-alpha inhibitor is administered parenterally.20. The method of claim 14, wherein said TNF-alpha inhibitor isadministered intramuscularly (i.m.), intravenously (i.v.),subcutaneously (s.c.) orally or rectally.
 21. The method of claim 20,wherein said TNF-alpha inhibitor is administered i.v. by injection orinfusion.
 22. The method of claim 20, wherein said TNF-alpha inhibitoris administered orally at a dosage of about 20 mg to about 1,500 mg. 23.The method of claim 14, wherein said TNF-alpha inhibitor is tetracyclineand is administered at a dosage of about 100 mg.
 24. The method of claim1, wherein said nerve disorder presents as sciatica.
 25. The method ofclaim 24, wherein the mammal is human.
 26. The method of claim 24,wherein the tetracycline or chemically modified tetracycline is selectedfrom the group consisting of: tetracycline, doxycycline lymecycline,oxytetracycline, minocycline, dedimethylaminotetracycline and bases andsalts thereof.
 27. The method of claim 24, wherein said TNF-alphainhibitor is administered systemically or locally.
 28. The method ofclaim 24, wherein said TNF-alpha inhibitor is administered parenterally.29. The method of claim 24, wherein said TNF-alpha inhibitor isadministered intramuscularly (i.m.), intravenously (i.v.),subcutaneously (s.c.) orally or rectally.
 30. The method of claim 29,wherein said TNF-alpha inhibitor is administered i.v. by injection orinfusion.
 31. The method of claim 29, wherein said TNF-alpha inhibitoris administered orally at a dosage of about 20 mg to about 1,500 mg. 32.The method of claim 24, wherein said TNF-alpha inhibitor is tetracyclineand is administered at a dosage of about 100 mg.
 33. The method of claim1, wherein said nerve disorder involves pain.
 34. The method of claim 1,wherein said TNF-α inhibitor is administered systemically or locally.35. The method of claim 1, wherein said TNF-α inhibitor is administeredparenterally.
 36. The method of claim 1, wherein said TNF-α inhibitor isadministered intramuscularly (i.m.), intravenously (i.v.),subcutaneously (s.c.), orally or rectally.
 37. The method of claim 36,wherein said TNF-α inhibitor is administered i.v. by injection orinfusion.
 38. The method of claim 36, wherein said TNF-α inhibitor isadministered orally at a dosage of about 20 mg to about 1,500 mg. 39.The method of claim 1, wherein said TNF-α inhibitor is a tetracyclineand is administered at a dosage of about 100 mg.